Repurposing Metformin in Nondiabetic People With HIV:Influence on Weight and Gut Microbiota

Background. People with HIV (PWH) taking antiretroviral therapy (ART) may experience weight gain, dyslipidemia, increased risk of non-AIDS comorbidities, and long-term alteration of the gut microbiota. Both low CD4/CD8 ratio and chronic inflammation have been associated with changes in the gut microbiota of PWH. The antidiabetic drug metformin has been shown to improve gut microbiota composition while decreasing weight and inflammation in diabetes and polycystic ovary syndrome. Nevertheless, it remains unknown whether metformin may benefit PWH receiving ART, especially those with a low CD4/CD8 ratio. Methods. In the Lilac pilot trial, we recruited 23 nondiabetic PWI I receiving ART for more than 2 years with a low CD4/CD8 ratio ( Results. Metformin decreased weight in PWH, and weight loss was inversely correlated with plasma levels of the satiety factor GDF-15. Furthermore, metformin changed the gut microbiota composition by increasing the abundance of anti-inflammatory bacteria such as butyrate-producing species and the protective Akkermansia muciniphila. Conclusions. Our study provides the first evidence that a 12-week metformin treatment decreased weight and favored anti-inflammatory bacteria abundance in the microbiota of nondiabetic ART-treated PWH. Larger randomized placebo-controlled clinical trials with longer metformin treatment will be needed to further investigate the role of metformin in reducing inflammation and the risk of non-AIDS comorbidities in ART-treated PWH

New Insight into Cerebrovascular Diseases

“Brain circulation is a true road map that consists of large extended navigation territories and a number of unimagined and undiscovered routes.” Dr. Patricia Bozzetto Ambrosi This book combines an update on the review of cerebrovascular diseases in the form of textbook chapters, which has been carefully reviewed by Dr. Patricia Bozzetto Ambrosi, Drs. Rufai Ahmad and Auwal Abdullahi and Dr. Amit Agrawal, high-performance academic editors with extensive experience in neurodisciplines, including neurology, neurosurgery, neuroscience, and neuroradiology, covering the best standards of neurological practice involving basic and clinical aspects of cerebrovascular diseases. Each topic was carefully revised and prepared using smooth, structured vocabulary, plus superb graphics and scientific illustrations. In emphasizing the most common aspects of cerebrovascular diseases: stroke burden, pathophysiology, hemodynamics, diagnosis, management, repair, and healing, the book is comprehensive but concise and should become the standard reference guide for this neurological approach

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

Development of Dual Reconstituted Humanized Mice for Studies of HIV-1 Neuropathogenesis

Extensive research have been conducted to dissect the rapidly evolving mechanism of human immunodeficiency virus (HIV-1) neuropathogenesis, and to investigate the viral reservoirs in the central nervous system (CNS), which is considered as a major barrier for the viral eradication. These efforts have been hindered due to the paucity of relevant animal models of progressive HIV-1 brain infections. Therefore, we developed a brand new mouse model reconstituted with both a human immune system and human glia (primarily astrocyte and oligodendrocyte lineage) in the brain. We transplanted newborn NOD/SCID/IL2Rγc−/− (NSG) mice with human neural progenitor cells (NPCs) in the lateral ventricle and hematopoietic stem cells (HSCs) in the liver at birth. Human astrocytes repopulated the white matter and periventricular mouse brain regions in an anatomically symmetrical manner, with the highest level of reconstitution in corpus callosum and periventricular region, and relatively low levels in other regions like frontal cortex, striatum and brain stem. Human glial engraftment induced transcriptional changes associated with multiple biological processes, including synaptic transportation, angiogenesis, and axon growth, ion channel activities, compared to non-reconstituted mice, as determined by next generation RNA sequencing. We then investigated the effects of HIV-1 infection on immune and glial cells pathological and molecular changes. The immune analyses of these HIV-1-infected mice showed increased meningeal and perivascular infiltration by human HLA-DR+ cells and surveillance by activated immune cells in brain tissue. The species-specific transcriptome analysis revealed alterations that were linked to interferon (IFN) type 1 and 2 signaling pathways (STAT1, 2, IRF9, MX1, ISG15, IFI6, CMPK2) and a range of host antiviral responses. Differentially expressed mouse genes in the hippocampus reflected tissue remodeling while down-regulated human genes were linked to altered cell growth, glial cytoskeleton reorganization, oligodendrocyte differentiation and myelin ensheathment (MBP, MOBP, PLP1, MAG and ZNF488). The results overlapped with the disease profile observed by others in human HIV-1 encephalitic brains. Therefore, this new model provided a promising future for study of human-specific viral-immune-glial interactions and discovery of new therapeutic targets for HIV-1 nervous system infection

Infectious Disease and the Diversification of the Human Genome

The human immune system is under great pathogen-mediated selective pressure. A combination of divergent infectious disease pathogenesis across human populations, and the overrepresentation of “immune genes” in genomic regions with signatures of positive selection suggests that pathogens have significantly altered the human genome. However, important features of the human immune system can confound searches for and interpretations of signatures of pathogen-mediated evolution. Immune system redundancy, immune gene pleiotropy, host ability to acquire immunity and alter the immune repertoire of their offspring through “priming”, and host microbiome complicate evolutionary interpretations of host- pathogen interactions. The overall promiscuity and sensitivity of the immune system to local environments can also muddy assumptions about the origins of a selective pressure on a given set of genes. This review addresses how features of the immune system, the primary buffer between a pathogen and the human genome, affect evolutionary signal. Here, considerations that must be made when assessing how pathogens have contributed to human diversification are addressed

Implication of Spiritual Network Support System in Epigenomic Modulation and Health Trajectory

With challenges in understanding the multifactorial etiologies of disease and individual treatment effect heterogeneities over the past four decades, much has been acquired on how physical, chemical and social environments a ffect human health, predisposing certain subpopulations to adverse health outcomes, especially the socio-environmentally disadvantaged (SED). Current translational data on gene and adverse environment interaction have revealed how adverse gene-environment interaction, termed aberrant epigenomic modulation, translates into impaired gene expression via messenger ribonucleic acid (mRNA) dysregulation, reflecting abnormal protein synthesis and hence dysfunctional cellular differentiation and maturation. The environmental influence on gene expression observed in most literature includes physical, chemical, physicochemical and recently social environment. However, data are limited on spiritual or religious environment network support systems, which reflect human psychosocial conditions and gene interaction. With this limited information, we aimed to examine the available data on spiritual activities characterized by prayers and meditation for a possible explanation of the nexus between the spiritual network support system (SNSS) as a component of psychosocial conditions, implicated in social signal transduction, and the gene expression correlate. With the intent to incorporate SNSS in human psychosocial conditions, we assessed the available data on bereavement, loss of spouse, loneliness, social isolation, low socio-economic status (SES), chronic stress, low social status, social adversity (SA) and early life stress (ELS), as surrogates for spiritual support network connectome. Adverse human psychosocial conditions have the tendency for impaired gene expression through an up-regulated conserved transcriptional response to adversity (CTRA) gene expression via social signal transduction, involving the sympathetic nervous system (SNS), beta-adrenergic receptors, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid response. This review specifically explored CTRA gene expression and the nuclear receptor subfamily 3 group C member 1 (NR3C1) gene, a glucocorticoid receptor gene, in response to stress and the impaired negative feedback, given allostatic overload as a result of prolonged and sustained stress and social isolation as well as the implied social interaction associated with religiosity. While more remains to be investigated on psychosocial and immune cell response and gene expression, current data on human models do implicate appropriate gene expression via the CTRA and NR3C1 gene in the SNSS as observed in meditation, yoga and thai-chi, implicated in malignant neoplasm remission. However, prospective epigenomic studies in this context are required in the disease causal pathway, prognosis and survival, as well as cautious optimism in the application of these findings in clinical and public health settings, due to unmeasured and potential confoundings implicated in these correlations

A systems biology approach to understand gut microbiota and host metabolism in morbid obesity: design of the BARIA Longitudinal Cohort Study

Introduction: Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. Methods: The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. Results: Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. Conclusion: The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic

Current Perspectives on Viral Disease Outbreaks

The COVID-19 pandemic has reminded the world that infectious diseases are still important. The last 40 years have experienced the emergence of new or resurging viral diseases such as AIDS, ebola, MERS, SARS, Zika, and others. These diseases display diverse epidemiologies ranging from sexual transmission to vector-borne transmission (or both, in the case of Zika). This book provides an overview of recent developments in the detection, monitoring, treatment, and control of several viral diseases that have caused recent epidemics or pandemics